DE102009001612A1 - Apparatus for generating constant pulsation free fluid flow for micro-fluidic applications, comprises reservoir, which is impinged with compressed gas with constant gas pressure - Google Patents

Abstract

The apparatus comprises a reservoir (1), which is impinged with a compressed gas (5) with constant gas pressure. The reservoir is connected with a drain pipe (7a-7h) in detachable manner for the flow of reaction fluid (6). A throttle (10a-10h) is arranged with specified flow resistance in the drain pipe. The quantity of the reaction fluid is determined by the flow resistance. The throttle has one or more capillaries, a fiber bundle or a fine porous body. The capillaries or fibers are made of glass, metal or plastic. The fine porous body is made of metal or plastic. An independent claim is also included for a method for generating a constant pulsation free fluid flow for micro-fluidic applications.

Description

object The invention relates to a method and an apparatus for producing constant pulsation-free liquid flows for microfluidic applications.

microfluidic Applications are gaining in importance in biochemistry and the Chemistry in production plants and for analytical purposes. Advantages of microfluidic applications in analytics are her low space requirement and low chemical consumption.

microfluidic Applications deal with the handling, regulation and behavior of Fluids, especially liquids in the smallest space, typically in the submillimeter range, e.g. B. ≤ 1 mm diameter for channels where the liquid guided, reactions etc.

The analytical monitoring of continuous processes is preferably carried out by a continuous titration. A continuous analysis also requires a continuous supply of the sample and the titrant. The continuous supply requires suitable pumps. A method and an apparatus for continuous titration is in DE 101 21 960 C1 described.

Also in microfluidic applications, the sample is transported and the titrant by pumping. For high precision continuous applications must have a larger one Period one or more very constant fluid flows are generated.

For the generation of liquid streams, the following pump types are known:
Piston or syringe pumps with a relatively small supply volume for the reagent of up to 20 ml, maximum 50 ml. Syringe pumps are characterized by a good dosing accuracy and reproducibility. The movement of the syringe plunger is usually carried out by means of a stepper motor, therefore, the dosage of the reagent is pulsating. If the syringe is empty, it must be refilled, which leads to frequent interruptions in the small storage volumes. If many fluid streams have to be generated at the same time, the outlay on space and costs will be unduly high.

diaphragm pumps are cheap pumps in the recent past specially developed for microfluidic systems. They promote speed or frequency-controlled small amounts of liquid according to the membrane stroke. However, they are caused by design strongly pulsating liquid flows. Another Disadvantage of the diaphragm pumae is a strong dependence the flow rate from the back pressure in the microfluidic system.

Peristalsis- or peristaltic pumps carry liquids through Fluid resistant elastic tubing. With them, even small flow rates, even multi-channel, promote. However, also here are design-related generates pulsating fluid flows. Furthermore Peristaltic pumps are expensive to buy.

Gear- and gerotor pumps are also common in microfluidics. They can also be used to overcome high back pressures if the delivery is sufficiently large. Indeed they also only pump liquids in a pulsating, are expensive and only available in a limited number of materials, so it may be aggressive with reagents too Corrosion problems can occur.

All These pumps have disadvantages when inexpensive pulse-free Liquid streams, especially in several Channels to be generated.

The The object of the invention is an inexpensive device and to find a method with the constant and pulsation-free Fluid streams for microfluidic applications, especially for analytical purposes.

These Task is described by the in the claims Device and the method solved.

The Liquid streams are generated by that a liquid volume located in a reservoir is pressurized with a pressurized gas at a constant pressure and the Amount of per unit time by one or more drain lines from the reservoir flowing liquid through a throttle located in the respective outflow line is determined with known flow resistance.

The Amount of liquid per unit of time through a capillary depends, depends on the geometry of the capillary, the viscosity of the liquid and the differential pressure between capillary inlet and outlet.

The flow velocity v of a (Newtonian) liquid with the dynamic viscosity η (eta) in a capillary with the radius r and the length l at a pressure difference Δp is given by the Hagen-Poiseuille law / 1 / v = π · r 4 Δp / (8 * I * η) / 1 /

The term f = (π * r ⁴ ) / (8 * I) is a shape factor given by the geometry of the capillary and corresponds to a resistance or a choke. If one chooses a throttle resistance, which is 10 to> 100 times higher than the resistance of the fluidic system, in which the liquid is to be pumped, the size of the liquid flow is essentially determined by the throttle resistance, in other words, pressure fluctuations in the fluidic system have no effect more on the amount of fluid pumped through the throttle. The amount of liquid flowing through the throttle per unit time remains constant (at constant pressure gas pressure). Equation / 1 / can be simplified too v = f · (1 / η) · Δp / 2 /

Summarizing the shape factor f and the reciprocal of the viscosity of the liquid to be delivered as a characteristic k, a simple proportional relationship between the pressure difference and the flow rate applies v = k · Δp / 3 /

Prefers you choose a choke resistance that is at least 10 times higher, preferably over 100 times higher is considered the resistance of the fluidic system in which the fluid is pumped. For simple analyzes with accuracy from 1% to 5%, choke resistances are 50 to 100 times higher for high-precision analysis should be 0.5 to 0.1% the throttle resistance is 1.00- 1000 times higher. Prefers Throttling resistors are 100 to 500 times higher than the resistance of the fluidic system. Will the throttle resistance more than 1000 times higher than the resistance of the fluidic system, so does the amount of liquid flowing through the restrictor more and more, so that the accuracy of analysis can suffer.

The Loading the liquid volume in the reservoir with pressurized gas can be one with one opposite the titration solution and the sample inert gas filled gas cylinder, z. B. a nitrogen cylinder, an argon bottle, an oxygen cylinder or from a pressurized gas network, the high pressure of up to to about 200 bar in these bottles via a suitable precise pressure reducing valve is reduced to a suitable working pressure. At the usual used in laboratories glass vessels and the used for microreactors other materials, eg. PMMA (polymethyl methacrylate), COC (cyclo-olefin copolymer), PC (Polycarbonate) have pressures of 1 to 6 bar for the admission of the liquid volume in the reservoir proven. When using storage containers, Of course, drain pipes and, if necessary, metal throttles can also be used higher pressures of up to 200 bar find use. Because of its transparency and corrosion resistance However, devices made of glass or plastic are preferred.

A particularly simple and therefore preferred method is the one needed Pressure in the storage vessel by evaporation of a low boiling compared to the liquid in the Supply reservoir inert liquid to produce which is not soluble in the liquid and whose Saturation vapor pressure at room temperature the desired Pressure in the storage vessel corresponds. In this case can be dispensed with the use of a pressure reducing valve. Under insoluble it is understood that nothing more as 1 wt .-% of the liquid or vapors in the liquid in the reservoir release under the pressure of the equilibrium pressure.

The Compressed gas for pressurizing the liquid volume in the Reservoir is usually transferred to the container fed to a corresponding compressed gas line.

at the use of low boiling liquids for Production of the compressed gas may be the low-boiling liquid be chosen so that their equilibrium pressure in the Operating temperature of the device, eg. B. of the analyzer, in usually the room temperature, the desired Pressure in the reservoir corresponds.

Suitable low-boiling liquids are for. B. n-butane (boiling point Kp = 0.5 ° C, saturation vapor pressure at room temperature (20 ° C) (p _RT = 2.08 bar), methyl chloride CH ₃ Cl (bp -24 ° C), butadiene (bp = -4.5 ° C), cyclopropane (bp = -33.5 ° C), butene-1 (bp = -6.3 ° C), 2 methyl propene (bp = -6.9 ° C) i-butane (bp = -12 ° C.) The skilled person is able to select numerous other suitable liquids on the basis of his specialist knowledge General criteria which the liquids have to fulfill are, as already mentioned, no solubility in the Liquid, no reaction with the liquid and for reasons of industrial hygiene no toxicity, eg vinyl chloride should not be used as it develops HCl with water and is carcinogenic.

Particularly suitable is n-butane, which develops a pressure of 2.08 bar at 20 ° C and a pressure of 2.14 bar at 21 ° C, i-butane with a saturation vapor pressure of 3 bar at 20 ° C or mixtures of n- and i-butane. Since they are lower in density than water, they can be added directly to the reservoir where they float on the liquid. As a result, it is possible to dispense with a pressure line in the container and it is possible to produce or use "disposable" containers in which the reaction liquid and the pressure are generated de fluid in common, so that the consumer has a particularly easy-to-use system in which the reservoir must be connected only via a suitable coupling with the drain line. The amount of pressure-generating liquid in the reservoir is to be dimensioned so that even with an empty container the conditions for the generation of an equilibrium vapor pressure are given, ie that still pressure-generating liquid is present in the reservoir.

In order to the titration liquid with constant volume flow and in an amount suitable for the analytical applications the drain line exits, is a throttle in the drain line present, which represents a flow resistance and the volume exiting the discharge line per unit of time to the desired for the particular application and required constant volume flow of usually 5 μl / h to 100 μl / h.

When Resistance to flow are suitable porous bodies, in particular sintered bodies of glass, metal, plastic or ceramics, fiber bundles (wicks), capillaries, bundles of capillaries or defined bottlenecks in the drainage line to be ordered. Bottlenecks can z. B. in glass pipes can be generated by heating the glass in the glass viscous state partially collapses, until only a small passage opening in the pipe is available. Also is with glass drain pipes Extracting the glass to a capillary possible.

porous Sintered body as a flow resistance can attached in the drain line by gluing or melting become. The latter applies in particular for sintered glass and Sintered ceramic body in glass pipes. The sintered bodies usually have pore sizes of 0.1 microns to 20 microns, they are available for purchase, z. B. at producers of filter pans and the like.

fiber bundles may be glass fibers, natural fibers, e.g. As cellulose or viscose fibers, or synthetic fibers consist. Suitable materials for synthetic fibers are z. As polyamide, polyester, fluorocarbon fibers, etc. The Fibers in fiber bundles generally have diameters of <1 to 100 microns.

The Thrush can also pass through a capillary or a bundle be formed by capillaries, z. B. in the drain line glued or through a bunch of each other fused, in particular made of glass capillaries, in a glass drain pipe can be melted down. The number and the inner diameter of these capillaries depends after printing in the storage vessel and the desired Liquid volume per unit time.

It is also possible, the entire drain pipe from a To form plastic capillary. Here are suitable as material for the capillaries because of their high resistance to breakage, especially plastics, z. B. FEP (PFEP, perfluoro (ethylene-propylene) polymer), PAEK (polyaryletherketone), PEEK (polyether ketone), ETFE (ethylene tetrafluoroethylene). such Capillaries have the advantage of shortening their throttling action the capillary without major aids easily can be reduced and adapted to the respective conditions.

The Invention will be further explained with reference to the figure.

It demonstrate:

1 schematically a storage vessel 1 that from a compressed gas tank 2 over the line 3 is pressurized. Into the line 3 is a pressure reducing valve 4 installed, with which the pressure in the gas space 5 of the storage vessel 1 to a desired value of 0.5 bar to 50 bar. In the storage vessel 1 is the reagent fluid 6 that have eight drainage pipes 7a to 7h in the fluid channel 8th a microfluidic system 9 be fed. In the drainage pipes 7a - 7h are chokes 10a to 10h , which have a flow resistance which corresponds to 100 times the flow resistance in the microfluidic system. In the microfluidic channel, mixing lines are located after each feed point 11a to 11h arranged, which also form a flow resistance. Frequently, the flow resistances of the mixing sections are negligibly small compared to the resistances of the reactors 10a -H.

The reduction in flow rate in the drain lines 7a to h is exclusively due to the ratio of the resistances of the mixing sections 11a ... h in the fluid channel 8th to that of the throttles 10a ... h and can easily be adapted to the circumstances. In most cases, a reduction in the flow rates in the lines of 2%, preferably less than 0.5% is tolerable.

In the system shown may be a change in flow velocity also be detected and compensated by calibration.

If in 1 the pressure vessel 2 is filled with a low-boiling liquid, which has a suitable saturated vapor pressure of preferably 2 to 6 bar at room temperature, can on the reducing valve 4 be waived.

2 shows another embodiment of the invention. Here, the required gas pressure is generated in the reservoir itself.

The storage tank 20 contains the reagent liquid 26 , over which a specifically lighter pressure generating fluid 28 , z. B. butane is located. The free gas space is with the gas developed from the pressure fluid 29 filled on the reagent liquid 26 with its equilibrium pressure acts. At the bottom of the storage tank 20 is a drainpipe 21 arranged with a shut-off valve 31 and a pressure-resistant coupling 32 is provided. The coupling 32 is sealing with a counterpart 33 connected via a line 34 which also has a shut-off valve 35 owns, in a distributor 36 which ends with four drainage pipes 27a ... d is provided. The drainage pipes 27a ... d are with chokes 30a ... d and are at their end with z. B. a Schlaucholive provided to facilitate the easy connection of a (not shown) tubing for feeding the reagent into a microfluidic system.

This embodiment allows easy replacement of the entire reagent / pressurization system and is particularly easy to handle. To further simplify the shut-off valves 31 and 35 be automatic valves, resulting in the coupling of the container 20 to the distributor 36 open automatically and close when disconnecting.

The throttles 10a ... h or 30a ... d need not necessarily be part of the distribution system, but the throttles can also be arranged in each case in the individual, connected to the distribution system supply lines of the reagent to the microfluidic system. If you keep a larger amount of supply lines with integrated throttle and defined if necessary. Different flow resistances in stock, an analysis device can be easily adapted and adapted to individual requirements or retrofitted.

Further It is possible to use a capillary against the reagent and to use the sample resistant plastic, its length is sized so that they have the desired throttle effect exercises. If such plastic capillaries are delivered with excess length, so you can easily by shortening individually be set to the desired throttle effect.

3 shows a part of a device according to the invention, the experiment by the liquid flows at a constant overpressure in the storage vessel 40 be measured. As chokes are porous ceramic pins 41a ... d used in the glass drain pipes 42a to 42d are melted and have a porosity of about 0.5 microns.

The reagent fluid 44 gets over the neck 43 with an overpressure of 1 bar (= absolute pressure 2 bar) acted upon.

4 shows the amounts of liquid per unit time at an overpressure of 1 bar from the drain lines 42a ... d exited. One sees a very good uniformity of the flow rates. By varying the length of the melting of the ceramic pins 41a ... d and the pressure can be generated in other limits pulsation-free liquid flows. If the ceramic pins are completely sealed in the glass tube, as in 1 and 2 As shown, the flow rate is controlled by variations in the length or porosity of the melted throttle body, besides a variation in pressure.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• - DE 10121960 C1 [0004]

Claims (14)

Device for generating constant pulsation-free liquid flows for microfluidic applications consisting of a reservoir containing a reaction liquid ( 1 ), which with a compressed gas ( 5 ) is acted upon by constant gas pressure and with at least one drain line ( 7a ... h) for the flow of the reaction liquid ( 6 ) is optionally releasably connected, wherein in the drain line a throttle ( 10a h) is arranged with known flow resistance, by which the amount of per unit time through the drain line ( 7a ... h) flowing reaction liquid is determined. Apparatus according to claim 1, characterized in that the container by means of a gas line ( 3 ) with an external compressed gas source ( 2 ) connected is. Device according to Claim 1 or 2, characterized that the compressed gas source evaporates from a room temperature at room temperature Liquid exists, whose with the liquid phase in equilibrium gas phase forms the compressed gas. Apparatus according to claim 3, characterized in that the evaporating liquid generating the compressed gas ( 28 ) in which the reaction liquid ( 26 ) reservoir ( 20 ) is located. Device according to claim 1, characterized in that the flow resistance of the throttle ( 10a h) is up to 1000 times, in particular 100 to 500 times larger than the flow resistance of the liquid in the microfluidic system ( 9 ) in the flow direction behind the throttle ( 10a ...H). Device according to claim 1, characterized in that that the choke consists of one or more capillaries, a fiber bundle or consists of a fine-pored body. Device according to claim 6, characterized in that that the capillaries or fibers are made of glass, one against the liquid inert plastic or metal. Device according to claim 6, characterized in that that the fine-pored body of sintered glass or a against the liquid inert plastic or metal body consists. Method for generating constant pulsation-free Fluid streams for microfluidic applications characterized in that a in a reservoir located liquid volume of a reaction liquid is pressurized with a pressurized gas at a constant pressure and the Amount of per unit time by one or more drain lines from the reservoir flowing reaction liquid by a throttle arranged in the respective outflow line is determined with known flow resistance. Method according to claim 9, characterized in that that the compressed gas by evaporation of a low-boiling liquid is generated and the constant pressure to the saturation vapor pressure over corresponds to the liquid. Method according to claim 10, characterized in that that the low-boiling liquid in which the liquid volume containing container is evaporated. Method according to claim 9, characterized in that that one uses a throttle whose flow resistance 10 times to 1000 times, especially 100 to 500 times larger is the flow resistance in the flow direction seen behind the throttle. Method according to claim 9, characterized in that that one uses a choke consisting of one or more capillaries, a fiber bundle or a fine-pored body consists. Method according to claim 13, characterized in that that one uses a choke consisting of one or more capillaries or fibers of glass, metal or plastic or a fine-pored body made of sintered glass, ceramic, metal or plastic.